In 1968, scientist Samuel Rahbar, MD, PhD, discovered that hemoglobin A1C, a protein in the blood, is elevated in people with diabetes. At the time, the only ways to determine glucose levels were through a blood glucose test in a lab or a urine test at home, but those were far from ideal. Neither provided information about long-term management of diabetes. Instead, they showed the glucose level at one point in time.

Rahbar was onto something with the A1C, but the research community needed a few decades to catch up. Important advancements followed in the ’70s, such as the first commercial A1C tests, but it wasn’t until 1993 that the A1C would change diabetes management forever. “The Diabetes Control and Complications Trial put hemoglobin A1C on the map,” says David Sacks, MB, ChB, FRCPath, a senior investigator at the National Institutes of Health.

The Diabetes Control and Complications Trial proved that the A1C can predict risk for diabetes complications in people with type 1 diabetes, and based on that data, researchers were able to develop blood glucose targets. “They said if your A1C is less than 7 percent, your risk for complications is very, very low,” says Sacks. The role of A1C measurement was further solidified a few years later, when the United Kingdom Prospective Diabetes Study proved that the A1C could also predict complications in people with type 2 diabetes.

The American Diabetes Association currently recommends that most adults with diabetes who are meeting treatment goals and have stable glucose levels get an A1C test at least twice a year. For people who are changing medications, adjusting therapy, or not meeting their blood glucose goals, an A1C test should be done quarterly. The test allows you to set goals and then acts as a baseline to adjust treatment to meet those targets.

But does the A1C tell us the whole story?

Beyond A1C

Science has shown that the A1C can predict a person’s risk for long-term diabetes complications, but it misses one important aspect of life with diabetes: low blood glucose (hypoglycemia). “The A1C is just an average, but it doesn’t tell you the fluctuation that’s happening to get to that average,” says Dace Trence, MD, FACE, director of the Endocrine and Diabetes Care Center at the University of Washington Medical Center in Seattle. “It doesn’t give the whole picture.”

Consider this: Your A1C of 7 percent may be an average of two to three months of stable blood glucose levels. But it could also be an average of high highs and low lows. Those hour-to-hour or day-to-day fluctuations in glucose—known as glucose variability—may increase short- and long-term health risks. The higher your glucose variability, for instance, the greater the risk for hypoglycemia and a severe hypoglycemic event, especially if you take insulin, says Irl Hirsch, MD, professor of medicine at the University of Washington School of Medicine.

Research supports this: A study published in 2012 in the journal Diabetes Technology and Therapeutics found a significant association between same-day and multiday glucose variability and risk of hypoglycemia among people with type 2 diabetes taking insulin. Other research shows that these fluctuations in glucose may cause a chemical imbalance in the body known as oxidative stress. “Oxidative stress is thought to be the main cause of the vascular complications of diabetes,” says Hirsch. A study published in 2006 in JAMA found that fluctuations in glucose triggered oxidative stress more than chronic high blood glucose.

Glucose swings don’t make you feel your best, either. “It’s interesting that patients will often share that they feel better when they don’t see the highs and the lows,” says Trence. “I frequently hear the comment, ‘I feel like I’ve come out of a mental fog.’ ”

Filling in Gaps

In the past, you may not have known if you were experiencing glucose swings, but new tools provide data that illuminate day-to-day ups and downs. Continuous glucose monitors (CGMs) track glucose levels around the clock. And the ambulatory glucose profile (AGP) condenses two weeks of finger-stick or, preferably, CGM glucose data into a 24-hour picture, which allows you and your doctor to pinpoint glucose variability.

Richard Bergenstal, MD, executive director of the Park Nicollet International Diabetes Center in Minneapolis, often uses CGM devices and AGP reports with his patients. Reviewing the data has helped him catch glucose swings in patients whose A1Cs were within their target range. It gives him the opportunity to adjust these patients’ treatment regimens to maintain their target A1Cs with more stable glucose levels.

Bergenstal isn’t the only one noticing the benefit of looking at additional measures to assess diabetes management. A “beyond A1C” movement is growing within the research community. An international group of scientists, health care providers, and patients is working to expand the use and standardization of continuous glucose monitoring in regulatory, research, and clinical settings. This would give a more comprehensive picture of blood glucose levels than A1C alone, according to an article published in Diabetes Care last June.

The Big Question

Glucose variability is important in predicting and avoiding short-term risks such as serious hypoglycemia. Less clear is whether glucose variability plays a role in predicting long-term complications beyond what the A1C already tells us. Right now, it’s a hypothesis with conflicting evidence, says Bergenstal, who published a point–counterpoint editorial with Hirsch in a 2015 issue of Diabetes Care.

A few studies have failed to establish glucose variability as a predictor of long-term complications. One study published in the June 2017 issue of Diabetes Care looked at finger-stick glucose data collected during the Diabetes Control and Complications Trial. The researchers collected thousands of glucose profiles over an average of 6½ years and gathered data on the progression of diabetes-related complications. “The study found that glucose variability did not appear to make a major difference beyond the impact of the A1C,” says John Lachin, ScD, research professor of biostatistics, epidemiology, and statistics at George Washington University and the study’s lead author. Hirsch notes, however, that this study lacks CGM data, which is the only way to show a true picture of glucose variability.

On the other side of the debate, several studies have established a connection between glucose variability and long-term complications. In one of the most cited, published in the October 2014 issue of Clinical Chemistry, researchers found that participants with the most glucose variability were more likely to have retinopathy and chronic kidney disease. There are limitations to this study, too: It’s a retrospective analysis, which means scientists analyze data from studies that have already been completed. These studies, while valuable, are generally considered to provide weaker evidence compared with studies that follow patients over time.

Future Focus

If the measurement of glucose variability has what it takes to reach gold-standard status like the A1C test, it will come down to one thing that researchers can agree on: rigorous studies. In a perfect world, scientists would do long-term clinical trials, like the Diabetes Control and Complications Trial, using CGMs or a closed-loop system.

For now, Bergenstal suggests talking with your doctor if you’ve been experiencing frequent lows or large fluctuations in your blood glucose levels. A loaner CGM from your health care provider may even be an option to get a more comprehensive look at your day-to-day glucose levels. “I believe everybody needs a picture, intermittently, of where their blood sugars are to make the best treatment decisions,” he says.

A1C Through the Ages

1968: Samuel Rahbar, MD, PhD, discovers that hemoglobin A1C is elevated in people with diabetes.

Late 1970s: The first commercial A1C tests become available.

1993: The Diabetes Control and Complications Trial proves that the A1C can predict long-term complication risk for people with type 1 diabetes.

1998: The United Kingdom Prospective Diabetes Study proves that the A1C can predict long-term complication risk for people with type 2 diabetes.